Translation of dipeptide repeat proteins in C9ORF72 ALS/FTD through unique and redundant AUG initiation codons
- University of Chicago, United States
- University of Massachusetts Medical School, United States
- Biogen, United States
Abstract
A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Translation of sense DPRs, such as poly-GA and poly-GR, depends on non-canonical (non-AUG) initiation codons. Here, we provide evidence for canonical AUG-dependent translation of two antisense DPRs, poly-PR and poly-PG. A single AUG is required for synthesis of poly-PR, one of the most toxic DPRs. Unexpectedly, we found redundancy between three AUG codons necessary for poly-PG translation. Further, the eukaryotic translation initiation factor 2D (EIF2D), which was previously implicated in sense DPR synthesis, is not required for AUG-dependent poly-PR or poly-PG translation, suggesting that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings on DPR synthesis from the C9ORF72 locus may be broadly applicable to many other nucleotide-repeat expansion disorders.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Paschalis Kratsios
Funding
Association for Frontotemporal Degeneration
- Paschalis Kratsios
National Institute of Neurological Disorders and Stroke (R37NS057553)
- Fen-Biao Gao
National Institute of Neurological Disorders and Stroke (R01NS101986)
- Fen-Biao Gao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Hugo J. Bellen, Baylor College of Medicine, United States
Version history
- Preprint posted: August 7, 2022 (view preprint)
- Received: September 2, 2022
- Accepted: September 6, 2023
- Accepted Manuscript published: September 7, 2023 (version 1)
- Version of Record published: September 29, 2023 (version 2)
Copyright
© 2023, Sonobe et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Translation of dipeptide repeat proteins in C9ORF72 ALS/FTD through unique and redundant AUG initiation codons
eLife 12:e83189.
https://doi.org/10.7554/eLife.83189
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